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1.
Molecules ; 28(2)2023 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-36677699

RESUMO

The present chemical investigation on the organic extract of the soft coral Sarcophyton cinereum has contributed to the isolation of four new cembranoids: 16ß- and 16α-hydroperoxyisosarcophytoxides (1 and 2), 16ß- and 16α-methoxyisosarcophytoxides (3 and 4), and a known cembranoid, lobocrasol (5). The structures of all isolates were elucidated by detailed spectroscopic analysis. Their structures were characterized by a 2,5-dihydrofuran moiety, of which the relative configuration was determined by DU8-based calculation for long-range coupling constants (4JH,H). The cytotoxicity and immunosuppressive activities of all isolates were evaluated in this study.


Assuntos
Antozoários , Diterpenos , Animais , Antozoários/química , Diterpenos/química , Estrutura Molecular
2.
Molecules ; 28(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36677851

RESUMO

Wedelia chinensis is a folk medicine used in many Asian countries to treat various ailments. Earlier investigations reported that the petroleum ether extract of the plant has potential biological activity, but the compounds responsible for activity are not yet completely known. Therefore, the current work was designed to isolate and characterize the compounds from the petroleum ether extract and to study their bioactivities. Four compounds including two diterepenes (-) kaur-16α-hydroxy-19-oic acid (1) and (-) kaur-16-en-19-oic acid (2), and two steroids ß-sitosterol (3), and cholesta-5,23-dien-3-ol (4) were isolated and characterized. Among the compounds, the diterpenes were found to have more biological activities than the steroidal compounds. Compound 1 showed the highest cytotoxicity with LC50 of 12.42 ± 0.87 µg/mL. Likewise, it possesses good antioxidant activity in terms of reducing power. On the contrary, compound 2 exerted the highest antiacetylcholinesterase and antibutyrylcholinesterase activity. Both the diterpenes showed almost similar antibacterial and antifungal activity. The identification of diterpenoid and steroid compounds with multifunctional activities suggests that W. chinensis may serve as an important source of bioactive compounds which should be further investigated in animal model for therapeutic potential in the treatment of different chronic diseases.


Assuntos
Diterpenos , Wedelia , Animais , Inibidores da Colinesterase/farmacologia , Antioxidantes/farmacologia , Antibacterianos , Extratos Vegetais/farmacologia
3.
Molecules ; 28(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36677967

RESUMO

A number of phytochemicals have been identified as promising drug molecules against a variety of diseases using an in-silico approach. The current research uses this approach to identify the phyto-derived drugs from Andrographis paniculata (Burm. f.) Wall. ex Nees (AP) for the treatment of diphtheria. In the present study, 18 bioactive molecules from Andrographis paniculata (obtained from the PubChem database) were docked against the diphtheria toxin using the AutoDock vina tool. Visualization of the top four molecules with the best dockscore, namely bisandrographolide (-10.4), andrographiside (-9.5), isoandrographolide (-9.4), and neoandrographolide (-9.1), helps gain a better understanding of the molecular interactions. Further screening using molecular dynamics simulation studies led to the identification of bisandrographolide and andrographiside as hit compounds. Investigation of pharmacokinetic properties, mainly ADMET, along with Lipinski's rule and binding affinity considerations, narrowed down the search for a potent drug to bisandrographolide, which was the only molecule to be negative for AMES toxicity. Thus, further modification of this compound followed by in vitro and in vivo studies can be used to examine itseffectiveness against diphtheria.


Assuntos
Andrographis , Corynebacterium diphtheriae , Difteria , Diterpenos , Andrographis paniculata , Andrographis/química , Diterpenos/farmacologia , Diterpenos/química , Extratos Vegetais/farmacologia , Compostos Fitoquímicos/farmacologia
4.
Phytomedicine ; 109: 154621, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36610139

RESUMO

BACKGROUND: Tripterygium wilfordii Hook. F (TWHF) is used as a traditional Chinese medicine, called thunder god vine, based on its efficacy for treating inflammatory diseases. However, its hepatotoxicity has limited its clinical application. Triptolide (TP) is the major active and toxic component of TWHF. Previous studies reported that a toxic pretreatment dose of TP leads to hepatic intolerance to exogenous lipopolysaccharide (LPS) stimulation, and to acute liver failure, in mice, but the immune mechanisms of TP-sensitised hepatocytes and the TP-induced excessive immune response to LPS stimulation are unknown. PURPOSE: To identify both the key immune cell population and mechanism involved in TP-induced hepatic intolerance of exogenous LPS. STUDY DESIGN: In vitro and in vivo experiments were conducted to investigate the inhibitory signal of natural killer (NK) cells maintained in hepatocytes, and the ability of TP to impair that signal. METHODS: Flow cytometry was performed to determine NK cell activity and hepatocyte histocompatibility complex (MHC) class I molecules expression; the severity of liver injury was determined based on blood chemistry values, and drug- or cell-mediated hepatocellular damage, by measuring lactate dehydrogenase (LDH) release. In vivo H-2Kb transduction was carried out using an adeno-associated viral vector. RESULTS: Interferon (IFN)-γ-mediated necroptosis occurred in C57BL/6N mice treated with 500 µg TP/kg and 0.1 mg LPS/kg to induce fulminant hepatitis. Primary hepatocytes pretreated with TP were more prone to necroptosis when exposed to recombinant murine IFN-γ. In mice administered TP and LPS, the intracellular IFN-γ levels of NK cells increased significantly. Subsequent study confirmed that NK cells were activated and resulted in potent hepatocellular toxicity. In vivo and in vitro TP administration significantly inhibited MHC class I molecules in murine hepatocytes. An in vitro analysis demonstrated the susceptibility of TP-pretreated hepatocytes to NK-cell-mediated cytotoxicity, an effect that was significantly attenuated by the induction of hepatocyte MHC-I molecules by IFN-α. In vivo induction or overexpression of hepatocyte MHC-I also protected mouse liver against TP and LPS-induced injury. CONCLUSION: The TP-induced inhibition of hepatocyte MHC-I molecules expression leads to hepatic intolerance to exogenous LPS and NK-cell mediated cytotoxicity against self-hepatocytes. These findings shed light on the toxicity of traditional Chinese medicines administered for their immunomodulatory effects.


Assuntos
Carcinoma Hepatocelular , Diterpenos , Neoplasias Hepáticas , Fenantrenos , Animais , Camundongos , Carcinoma Hepatocelular/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais , Lipopolissacarídeos , Neoplasias Hepáticas/metabolismo , Camundongos Endogâmicos C57BL , Fenantrenos/farmacologia , Diterpenos/farmacologia
5.
Phytomedicine ; 109: 154537, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36610122

RESUMO

BACKGROUND: The presence or absence of damage to the liver organ is crucial to a person's health. Nutritional disorders, alcohol consumption, and drug abuse are the main causes of liver disease. Liver transplantation is the last irrevocable option for liver disease and has become a serious economic burden worldwide. Andrographolide (AP) is one of the main active ingredients of Herba Andrographitis. It has several biological activities and has been reported to have protective and therapeutic effects against liver diseases. Earlier literature has been written on AP's role in treating inflammation and other diseases, and there has not been a systematic review on liver diseases. This review is dedicated to sorting out the research results of AP against liver diseases. Pharmacokinetics, toxicity, and nanotechnology to improve bioavailability are discussed. Finally, an outlook and assessment of its future are provided. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. PubMed and web of Science databases were used to search all relevant literature on AP for liver disease up to 2022. RESULTS: Studies have shown that AP plays an important role in different liver disease phenotypes, mainly through anti-inflammatory and antioxidant activities. AP regulates HO-1 and inhibits hepatitis virus replication. It affects the NF-κB pathway, downregulates inflammatory factors such as IL-1ß, IL-6, and TNF-α, and reduces liver damage. In preventing liver fibrosis, AP inhibits angiogenesis and activation of hepatic stellate cells and reduces oxidative stress involved in the Nrf2 and TGF-ß1/Smad pathways. In addition, AP impedes the development of liver cancer by promoting apoptosis and autonomous phagocytosis in a cell-dependent way. Interestingly, miRNAs are involved in the therapeutic process of liver cancer and hepatic fibrosis. The poor solubility of AP limits the development of dosage forms. Therefore, the advent of nanoformulations has improved bioavailability. Although the effect of AP is dose- and time-dependent, the magnitude of its toxicity is not negligible. Some clinical trials have shown that AP has mild side effects. CONCLUSIONS: AP, as an effective natural product, has a good effect on the liver disease through multiple pathways and targets. However, the dose reaches a certain level, leading to its toxicity and side effects. For better clinical application of AP, high-quality clinical and toxic intervention mechanisms are needed to validate current studies. In addition, modulation of miRNA-mediated hepatocellular carcinoma and liver fibrosis and synergistic action with drugs may be the future focus of AP. In conclusion, AP can be regarded as an important candidate for treating different liver diseases in the future.


Assuntos
Diterpenos , Neoplasias Hepáticas , Humanos , Fígado , Cirrose Hepática/tratamento farmacológico , Diterpenos/farmacologia , Diterpenos/uso terapêutico , NF-kappa B/metabolismo , Neoplasias Hepáticas/tratamento farmacológico
6.
Phytomedicine ; 109: 154575, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36610163

RESUMO

BACKGROUND: High levels of glycolysis supply large quantities of energy and biological macromolecular raw materials for cell proliferation. Triptolide (TP) is a kind of epoxy diterpene lactone extracted from the roots, flowers, leaves, or grains of the Celastraceae plant, Tripterygium wilfordii. TP has multiple biological activities, including anti-inflammatory, immunologic suppression, and anti-cancer effects. Nevertheless, it is little known regarding its anti-intrahepatic cholangiocarcinoma (ICC) growth, and the mechanism still require exploration. PURPOSE: This research explored the effect of TP on ICC growth and investigated whether TP inhibits glycolysis via the AKT/mTOR pathway. METHODS: Cell proliferation was analyzed by Cell Counting Kit-8 (CCK-8), clonogenic assay, and flow cytometry. The underlying molecular mechanism was identified by determining glucose consumption, ATP production, lactate production, hexokinase (HK) and pyruvate kinase (PK) activity, and Western blot analysis. A rapid ICC model of AKT/YapS127A oncogene coactivation in mice was used to clarify the effect of TP treatment on tumor growth and glycolysis. RESULTS: The results showed that TP treatment significantly inhibited ICC cell proliferation and glycolysis in a dose- and time-dependent manner(P < 0.05). Further analysis suggested that TP suppressed ICC cell glycolysis by targeting AKT/mTOR signaling. Additionally, we found that TP inhibits tumor growth and glycolysis in AKT/YapS127A mice(P < 0.05). CONCLUSION: Taken together, we revealed that TP suppressed ICC growth by suppressing glycolysis via the AKT/mTOR pathway and may provide a potential therapeutic target for ICC treatment.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Diterpenos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Colangiocarcinoma/metabolismo , Proliferação de Células , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Glicólise , Linhagem Celular Tumoral
7.
J Ethnopharmacol ; 305: 116109, 2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-36587877

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Qifu decoction (QFD) is a famous traditional Chinese medicine (TCM) composed of Astragali Radix (HuangQi) and Aconiti Lateralis Radix Praeparaia (Fuzi), which can alleviate doxorubicin (DOX)-induced cardiotoxicity (DIC). However, its protective mechanism remains obscured. AIM OF THE STUDY: The present study aimed to uncover the cardioprotective mechanism and the synergistic effect of QFD against DIC in mice. MATERIALS AND METHODS: The cardioprotective activity of QFD against DIC was assessed by electrocardiogram, serum biochemical assays and histopathology. Mass spectrometry-based metabolomic approach was conducted to elucidate the preventive mechanisms of QFD, HuangQi decoction (HQD), and Fuzi decoction (FZD) against DIC. QFD, HQD, FZD-targeted metabolic pathways were identified and compared to investigate the synergistic mechanism of QFD by computational systems analysis. Quantitative real-time PCR (qRT-PCR) was further employed to validate the key metabolic pathways at the level of the gene. RESULTS: The electrocardiogram combined with the biochemical analysis and histopathology showed that the protection effects were sorted as QFD > HQD ≈ FZD. A total of 41 metabolites contributing to DIC were identified in the mice serum, among which 32, 12 and 10 metabolites were significantly reverted by QFD, HQD and FZD, respectively. Metabolic pathway analysis revealed that DOX perturbed 12 metabolic pathways, and QFD, HQD, and FZD-treated groups could significantly reverse 12, 7 and 6 metabolic pathways of these 12 metabolic pathways. Metabolic pathway and qRT-PCR revealed that QFD could protect DIC mainly by regulating energy metabolism, amino acids metabolism, arachidonic acid metabolism and glycerophospholipid metabolism, and HQD and FZD mutually reinforced each other. CONCLUSION: These evidences revealed that QFD was a promising drug candidate for DIC by maintaining metabolic homeostasis. Meanwhile, this work provided a useful approach for evaluating the efficacy and the synergistic effects of TCMs against cardiomyopathy.


Assuntos
Diterpenos , Medicamentos de Ervas Chinesas , Camundongos , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/química , Doxorrubicina/toxicidade , Espectrometria de Massas , Metabolômica
8.
J Ethnopharmacol ; 305: 116124, 2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-36587880

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Callicarpa longissima is a typical Yao ethnomedicine that has been used to treat arthritis in China. Our previous study found that the dichloromethane extract (DCME) of C. longissima showed anti-inflammatory activity in vitro. However, the anti-inflammatory mechanism and detailed chemical composition of DCME remain unclear, which lead to the original interest of this study. AIM OF THE STUDY: The study aimed to evaluate the anti-inflammatory properties of the DCME from C. longissima and further explore the accurate chemical components responsible for this active extract. MATERIALS AND METHODS: The anti-inflammatory activity of DCME in vivo was tested with carrageenan-induced mice paw edema model. Its anti-inflammatory mechanism was explored with LPS-stimulated RAW264.7 macrophages model. The compounds in DCME were isolated by repeated column chromatography and their structures were identified on the basis of nuclear magnetic resonance spectroscopy. The anti-inflammatory activities of the isolates in vitro were also tested by suppressing releases of inflammatory mediators (NO, IL-6 and TNF-α) in RAW264.7 macrophages model. In addition, the molecular docking analysis, which evaluated the potential interaction between the compounds and Toll-like receptor 4 (TLR4) and nuclear factor κB (NF-κB), was performed. RESULTS: DCME effectively alleviated the mice paw edema induced by carrageenan. In LPS-stimulated RAW264.7 cells, DCME significantly decreased the production of interleukin (IL)-6 and tumor necrosis factor α (TNF-α) via inhibiting their mRNA transcription, down-regulated the expression of TLR4 and myeloid differentiation factor 88, inhibited the phosphorylation of alpha inhibitor of NF-κB (IκBα), NF-κB p65, and degradation of IκBα. Twelve diterpenoid phenols were identified from DCME, and they not only showed different inhibitory effects on the production of NO, IL-6 and TNF-α in LPS-stimulated RAW264.7 cells, but also could bind to TLR4 and NF-κB as analyzed by molecular docking. CONCLUSIONS: Taken together, DCME from C. longissima could inhibit inflammatory response both in vitro and in vivo, which is mainly attributed to the synergistic effect of abundant diterpenoid phenols through inhibiting the TLR4/NF-κB signaling pathway, and might be a promising agent for the treatment of inflammatory diseases.


Assuntos
Callicarpa , Diterpenos , Animais , Camundongos , NF-kappa B/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Cloreto de Metileno/efeitos adversos , Interleucina-6/metabolismo , Carragenina/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Receptor 4 Toll-Like/metabolismo , Lipopolissacarídeos/farmacologia , Simulação de Acoplamento Molecular , Transdução de Sinais , Anti-Inflamatórios/efeitos adversos , Diterpenos/farmacologia , Edema/induzido quimicamente , Edema/tratamento farmacológico
9.
Int J Mol Sci ; 24(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36674604

RESUMO

Ten jatrophane diterpenoids were isolated from the whole plant Euphorbia peplus Linn. including seven new ones, named euphjatrophanes A-G (labeled compounds 1, 2, 4-8). Their structures were elucidated with a combination of spectroscopic and single-crystal X-ray crystallography, enabling the identification of compounds 3, 9, and 10 as the previously published euphpepluones G, K, and L, respectively. All compounds were evaluated for their bioactivity with flow cytometry in assays of autophagic flux in HM Cherry-GFP-LC3 (human microglia cells stably expressing the tandem monomeric mCherry-GFP-tagged LC3) cells. Euphpepluone K (9) significantly activated autophagic flux, an effect that was verified with confocal analysis. Moreover, cellular assays showed that euphpepluone K (9) induced autophagy and inhibited Tau pathology.


Assuntos
Diterpenos , Euphorbia , Humanos , Estrutura Molecular , Diterpenos/farmacologia , Diterpenos/química , Autofagia
10.
Int J Mol Sci ; 24(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36674622

RESUMO

In Octodon degus, the aging process is not equivalent between sexes and worsens for females. To determine the beginning of detrimental features in females and the ways in which to improve them, we compared adult females (36 months old) and aged females (72 months old) treated with Andrographolide (ANDRO), the primary ingredient in Andrographis paniculata. Our behavioral data demonstrated that age does not affect recognition memory and preference for novel experiences, but ANDRO increases these at both ages. Sociability was also not affected by age; however, social recognition and long-term memory were lower in the aged females than adults but were restored with ANDRO. The synaptic physiology data from brain slices showed that adults have more basal synaptic efficiency than aged degus; however, ANDRO reduced basal activity in adults, while it increased long-term potentiation (LTP). Instead, ANDRO increased the basal synaptic activity and LTP in aged females. Age-dependent changes were also observed in synaptic proteins, where aged females have higher synaptotagmin (SYT) and lower postsynaptic density protein-95 (PSD95) levels than adults. ANDRO increased the N-methyl D-aspartate receptor subtype 2B (NR2B) at both ages and the PSD95 and Homer1 only in the aged. Thus, females exposed to long-term ANDRO administration show improved complex behaviors related to age-detrimental effects, modulating mechanisms of synaptic transmission, and proteins.


Assuntos
Diterpenos , Octodon , Animais , Feminino , Octodon/metabolismo , Encéfalo/metabolismo , Diterpenos/farmacologia , Diterpenos/metabolismo , Reconhecimento Psicológico
11.
Int J Mol Sci ; 24(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36674639

RESUMO

A new family of diterpene-type aminotriol derivatives has been synthesised from stevioside in a stereoselective manner. The key intermediate spiro-epoxide was prepared through the methyl ester of the allilyc diol derived from steviol. The oxirane ring was opened with primary and secondary amines, providing a versatile library of aminotriols. The corresponding primary aminotriol was formed by palladium-catalysed hydrogenation, and an N,O-heterocyclic compound was synthesised in a regioselective reaction. All new compounds were characterised by 1D- and 2D-NMR techniques and HRMS measurements. In our in vitro investigations, we found that the aromatic N-substituted derivatives exhibited high inhibition of cell growth on human cancer cell lines (HeLa, SiHa, A2780, MCF-7 and MDA-MB-231). The antiproliferative activities were assayed by the MTT method. Furthermore, the introduction of an additional hydroxy group slightly increased the biological activity. The drug-likeness of the compounds was assessed by in silico and experimental physicochemical characterisations, completed by kinetic aqueous solubility and in vitro intestinal-specific parallel artificial membrane permeability assay (PAMPA-GI) measurements.


Assuntos
Antineoplásicos , Diterpenos , Neoplasias Ovarianas , Feminino , Humanos , Linhagem Celular Tumoral , Diterpenos/farmacologia , Células HeLa , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/química , Relação Estrutura-Atividade , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais
12.
Int J Mol Sci ; 24(2)2023 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-36674768

RESUMO

Continuing chemical investigation of the Red Sea sponge Spongia sp. led to the isolation of four new 3,4-seco-3,19-dinorspongian diterpenoid lactones, secodinorspongins A-D (1-4), along with a classical spongian diterpenoid lactone, sponginolide (5). The chemical structures, including the absolute configurations of these compounds, were elucidated using the extensive spectroscopic study composed of 1D and 2D NMR data analyses, and a comparison between calculated-electronic-circular-dichroism (ECD) and experimental-circular-dichroism (CD) spectra. A plausible biosynthetic pathway of 1-4 was also proposed. Furthermore, the cytotoxicity, antibacterial and anti-inflammatory activities of 1-5 were evaluated. Compound 1 was found to exhibit inhibitory activity against the growth of Staphylococcus aureus (S. aureus), and 4 and 5 exhibited suppression of superoxide-anion generation and elastase release in fMLF/CB-induced human neutrophils.


Assuntos
Diterpenos , Poríferos , Animais , Humanos , Lactonas , Staphylococcus aureus , Estrutura Molecular , Poríferos/química , Diterpenos/química
13.
Nat Commun ; 14(1): 343, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36670101

RESUMO

The spatial organization of genes within plant genomes can drive evolution of specialized metabolic pathways. Terpenoids are important specialized metabolites in plants with diverse adaptive functions that enable environmental interactions. Here, we report the genome assemblies of Prunella vulgaris, Plectranthus barbatus, and Leonotis leonurus. We investigate the origin and subsequent evolution of a diterpenoid biosynthetic gene cluster (BGC) together with other seven species within the Lamiaceae (mint) family. Based on core genes found in the BGCs of all species examined across the Lamiaceae, we predict a simplified version of this cluster evolved in an early Lamiaceae ancestor. The current composition of the extant BGCs highlights the dynamic nature of its evolution. We elucidate the terpene backbones generated by the Callicarpa americana BGC enzymes, including miltiradiene and the terpene (+)-kaurene, and show oxidization activities of BGC cytochrome P450s. Our work reveals the fluid nature of BGC assembly and the importance of genome structure in contributing to the origin of metabolites.


Assuntos
Diterpenos , Lamiaceae , Lamiaceae/genética , Lamiaceae/metabolismo , Diterpenos/metabolismo , Terpenos/metabolismo , Família Multigênica , Vias Biossintéticas/genética
14.
Chem Biodivers ; 20(1): e202200999, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36484459

RESUMO

Five unknown labdane diterpenoids Stevelins A-E (1-5), three known labdane diterpenoids (6-8) and three labdane norditerpenoids (9-11) were isolated from the Stevia rebaudiana. The structures were determined primarily via NMR spectroscopic data and HR-ESI-MS experiments. X-ray crystallography using CuKα radiation was used to determine the absolute configurations of 1, and the absolute configurations of 2-5 were deduced by electronic circular dichroism (ECD) calculations. The potential anti-atherosclerosis activities of all compounds were evaluated by measuring their inhibitory effects on the macrophage foam cell formation. As a result, most isolated compounds could significantly inhibit oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation, which suggests that these compounds may be promising candidates in the treatment for atherosclerosis.


Assuntos
Diterpenos , Stevia , Estrutura Molecular , Diterpenos/farmacologia , Diterpenos/química , Espectroscopia de Ressonância Magnética , Dicroísmo Circular
15.
Chem Biodivers ; 20(1): e202201065, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36514858

RESUMO

Marine octocorals belonging to the genus Cladiella, usually encountered on reefs in the Indo-Pacific region, have been proven to be rich sources of diverse secondary metabolites with intriguing structural features and promising bioactivities. In this review, 155 compounds from six unambiguously identified C. krempfi, C. australis, C. pachyclados, C. hirsuta, C. tuberculosa, C. conifera, together with several unidentified Cladiella spp. are summarized covering the literatures from 2006 to August 2022. It is noteworthy that diterpenoids dominated the secondary metabolite profile of this genus counting for 78 %. Structurally, the majority of these diterpenes belonged to eunicellan family characterized by different patterns of ether linkage. The impacts of these chemical compositions on an array of potential pharmacological activities were also reviewed, giving an overview of the potential application of Cladiella secondary metabolites.


Assuntos
Antozoários , Diterpenos , Animais , Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Diterpenos/química , Antozoários/química
16.
J Am Chem Soc ; 145(1): 311-321, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36538760

RESUMO

A unified strategy toward asymmetric divergent syntheses of nine C8-ethano-bridged diterpenoids A1-A9 (candol A, powerol, sicanadiol, epi-candol A, atisirene, ent-atisan-16α-ol, 4-decarboxy-4-methyl-GA12, trachinol, and ent-beyerane) has been developed based on late-stage transformations of common synthons having ent-kaurane and ent-trachylobane cores. The expeditious assembly of crucial advanced ent-kaurane- and ent-trachylobane-type building blocks is strategically explored through a regioselective and diastereoselective Fe-mediated hydrogen atom transfer (HAT) 6-exo-trig cyclization of the alkene/enone and 3-exo-trig cyclization of the alkene/ketone, showing the multi-reactivity of densely functionalized polycyclic substrates with πC═C and πC═O systems in HAT-initiated reactions. Following the rapid construction of five major structural skeletons (ent-kaurane-, ent-atisane-, ent-beyerane-, ent-trachylobane-, and ent-gibberellane-type), nine C8-ethano-bridged diterpenoids A1-A9 could be accessed in the longest linear 8 to 11 steps starting from readily available chiral γ-cyclogeraniol 1 and known chiral γ-substituted cyclohexenone 2, in which enantioselective total syntheses of candol A (A1, 8 steps), powerol (A2, 9 steps), sicanadiol (A3, 10 steps), epi-candol A (A4, 8 steps), ent-atisan-16α-ol (A6, 11 steps), and trachinol (A8, 10 steps) are achieved for the first time.


Assuntos
Diterpenos do Tipo Caurano , Diterpenos
17.
Pharm Biol ; 61(1): 61-68, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36548192

RESUMO

CONTEXT: Andrographolide (Andr) is a bioactive Andr diterpenoid extracted from herbaceous Andrographis paniculata (Burm. F.) Wall. ex Nees (Acanthaceae). Andr can relieve cardiac dysfunction in mice by inhibiting the mitogen-activated protein kinases (MAPK) pathway. OBJECTIVE: This study investigates the efficacy and underlying mechanism of Andr on cardiac hypertrophy in mice. MATERIALS AND METHODS: Male C57 mice (20-25 g, 6-8 weeks) were divided into four groups (n = 10 mice/group) as sham group (sham operation), transverse aortic constriction (TAC) model group, TAC + Andr 100 mg/kg group and TAC + Andr 200 mg/kg group. Andr groups were given intragastric administration of Andr (100 and 200 mg/kg) once a day for 14 consecutive days. An in vitro hypertrophy model was established by adding 1 µM of Ang II to H9c2 cells for 48 h induction. RESULTS: In TAC-mice, Andr improved echocardiographic indices [reduced LVESD (30.4% or 37.1%) and LVEDD (24.8% or 26.4%), increased EF (22.9% or 42.6%) and FS (25.4% or 52.2%)], reduced BNP (11.5% or 23.6%) and Ang II levels (10.3% or 32.8%), attenuates cardiac fibrosis and reduces cardiac cell apoptosis in TAC mice. In vitro, Andr attenuated cardiomyocyte hypertrophy and decreased the protein expression of GRP78 (67.8%), GRP94 (47.6%), p-PERK (44.9%) and CHOP (66.8%) in Ang-II-induced H9c2 cells and reversed after endoplasmic reticulum (ER) stress agonist Tunicamycin (TN) treatment. DISCUSSION AND CONCLUSIONS: Andr was found to be an anti-hypertrophic regulator, which could attenuate cardiac hypertrophy by suppressing ER stress. It may be a new therapeutic drug for cardiac hypertrophy.


Assuntos
Cardiomegalia , Diterpenos , Animais , Masculino , Camundongos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Estresse do Retículo Endoplasmático , Fibrose , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia
18.
J Pharm Biomed Anal ; 224: 115200, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36563593

RESUMO

Xylopic acid (XA) is a bioactive diterpene kaurene isolate of the Guinea pepper fruit, Xylopia aethiopica (Annonaceae) with numerous well-established biological effects. In this study, we aimed to fill certain scientific voids in terms of the scientific literature on XA, specifically, its pharmacokinetic (PK) parameters and in vitro liver microsomal enzyme metabolism. A new LC-MS/MS method was developed and validated for the determination of the plasma concentration-time profile of XA. The method was found to be accurate, precise, selective and repeatable with lowest limit of quantification (LLOQ) of 10 ng/mL and run time of 15 min. The maximum plasma concentration (Cmax), time at which maximum plasma concentration was attained (Tmax), half-life (t1/2), clearance (CL) and mean residence time (MRT) of XA were 167.03 ± 6.18 ng/mL; 10 h; 13.03 ± 7.33 h; 0.04 ± 0.01 mL/h/kg and 23.83 ± 11.02 h respectively. Six metabolites (M1-M6) were tentatively identified after XA was subjected to in vitro liver microsomal enzyme metabolism. The metabolites were the products of methylation (M1), glucuronidation (M2), deacetylation (M3), glucosylation (M4), hydroxylation and glutamic acid addition (M5) and glutathionylation (M6). The outcome of this study provides useful insights that could guide further research on XA.


Assuntos
Diterpenos , Espectrometria de Massas em Tandem , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Fígado , Microssomos Hepáticos
19.
Phytochemistry ; 206: 113549, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36481314

RESUMO

A detailed chemical investigation of the South China Sea soft coral Sarcophyton ehrenbergi has yield seven undescribed cembranoids, namely isoehrenbergol D and sarcoehrenolides F-K embodying a rare α,ß-unsaturated-lactone moiety at C-6 to C-19, along with two known related compounds, ehrenbergol D and sarcoehrenolide A. Their structures and absolute configurations were unambiguously established in the light of extensive spectroscopic data analysis, modified Mosher's method, X-ray diffraction analysis, and quantum chemical computation method. In a bioassay for α-glucosidase inhibition, ehrenbergol D was evaluated as α-glucosidase inhibitor with an IC50 value of 13.57 µM.


Assuntos
Antozoários , Diterpenos , Animais , Antozoários/química , Diterpenos/farmacologia , Diterpenos/química , Cristalografia por Raios X , Análise Espectral , China , Estrutura Molecular
20.
Phytochemistry ; 206: 113512, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36503704

RESUMO

Eight unreported α-acyloxy amide substituted kalihinane diterpenes, named kalihiacyloxyamides A-H were isolated from the South China Sea sponge Acanthella cavernosa. The planar structures and absolute configurations were elucidated by detailed 1D and 2D NMR experiments along with HRESIMS analysis, single crystal X-ray diffraction and CD spectroscopic analysis. Two compounds showed significant cytotoxicity against K562 cell line with IC50 values of 6.4 and 6.3 µM, while two other compounds displayed moderate cytotoxicity against MDA-MB-231 with IC50 values of 7.3 and 7.9 µM.


Assuntos
Diterpenos , Diterpenos/farmacologia , Diterpenos/química , Espectroscopia de Ressonância Magnética , Linhagem Celular , China , Estrutura Molecular
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